Some articles which are very sensitive to the temperature, such as most of vaccines, biological products, bioactive samples, some medicines and the like as well as fresh foods such as fresh milk, milk product, fresh meat, fresh fish and the like, need to be stored and transported at low temperature. For a long time, it is a main method for ensuring the safety of these articles/products, especially medicines or foods, to label the valid period, the quality guarantee period or the fresh preservation period. However, these methods can seldom suggest that whether those medicines or foods which need to be stored and transported at low temperature have been exposed to a temperature exceeding the safe storage and transport temperature for a too long time. The use safety and the use of various thermally sensitive articles can be better ensured by using a simple and inexpensive method to accurately indicate whether the thermally sensitive articles, such as fresh food, vaccines (usually between 2° C. and 8° C.), bioactive samples and the like which need low temperature storage, deteriorate, fail or lose activity during the storage or transport because the safe storage and transport temperature is exceeded.
In 1990s, the World Health Organization (WHO) began to pay attention to the problem that vaccines are overheated during the cold chain storage and transport, because this will lead to a decrease in the immune effect of the vaccines, reducing the protection of vaccines for children. Subsequently, the WHO called for the development of a tag which is easy to use and inexpensive so as to accurately reflect the thermal history of vaccines from leaving the factory after manufacture, being transported and stored, to reaching end users. The essential requirements for the tag are as follows: 1. it may give accurate indication to restrict the use of vaccines overheated; 2. it has a small volume, and may be sticked onto a vaccine bottle, an ampoule or an injector; 3. it is stable and reliable during the whole process from production to actual use; 4. it is suitable for mass production, is inexpensive and meets the global demand for vaccines of United Nations International Children's Emergency Fund.
In 1996, the TempTime company (the predecessor of which is Lifelines), USA developed a tag for the first time which can meet the requirements of WHO, and the tag is applied to the polio vaccines produced by three vaccine manufacturers, i.e., GlaxoSmithKline, Sanofi-Pasteur and Novartis. The tags provided by Temptime are classified into three categories according to the function thereof. The first one is Critical Temperature Indicator (CTI), which immediately changes colour once the set value of temperature is exceeded. The second one is Critical Temperature-Time Indicator (CTTI), the colour change of which delays to some extent, and which changes colour after exposing to a temperature above the set value for several minutes or tens of minutes. The third one is known as Time-Temperature Indicator (TTI), having a longer response time, in which the temperature sensing material changes colour after receiving certain amount of heat, and this kind of tag is a tag suitable for indicating the thermal history of vaccines.
Currently, there are hundreds of patents related to Time-Temperature Indicators in the world. These patented technologies can be classified into mechanical type, chemical type, enzyme reaction type, microorganism type, polymer type, electronic chemical type, diffusion type and the like according to the operating principles of the products. These technologies are mainly based on mechanical property, electrical property, diffusion property, bio-enzyme reaction, polymerization and the like of the materials. There are mainly three kinds of TTI tags which are more mature and already commercialized: polymer type, enzyme reaction type and diffusion type.
The polymer type is developed by TempTime company, USA, and mainly based on that a coloured polymer is produced by the solid state 1,4-addition polymerization of a substituted diacetylene derivative. The rate of this polymerization increases as the temperature rises, and the produced polymer makes the colour darker continuously. By comparison with the colour of surroundings, it is indicated whether the vaccines have been overheated. It is required to screen and synthesize suitable monomer for such a tag, and the tag need to be stored at −18° C. or below after its production, which obviously increases the use cost of the tag.
Early indicator of enzyme reaction type is essentially a kind of pH indicator, which indicates the temperature history or heating history by measuring the colour change caused by the pH value change of the medium which is caused by the protons H+ released from the enzyme-catalyzed hydrolysis of lipids substrate. The enzymatic hydrolysis becomes faster as the temperature rises, and thus the release rate of protons also becomes faster. A typical one is Vitsab ring indicator developed by a Swedish company.
A typical product of earlier diffusion type time-temperature indicator is 3M Monitor Mark indicator produced by 3M company, USA, which is based on the diffusion of the dye on a string, and the temperature indicating range and response time of which depends on the type of dyes. Another form of diffusion type indicator is prepared by coating a porous substrate with a material having specific melting point. The optical refractive indexes of the substrate and the material are close to each other. When the material melts at a temperature above specific temperature and diffuses into the porous substrate, the transmittance of the substrate increases after the air in the pores of the substrate is exhausted, and thus a colour change is achieved, showing the heating process.
Currently, WHO classifies nearly twenty vaccines into 4 categories according to their stability: the most unstable vaccines, unstable vaccines, stable vaccines and highly stable vaccines, and thus proposes the technical requirements for corresponding time-temperature indicators. The technical standards thus established takes the properties of indicator products in the prior art into account, but do not depend on the thermal stability of vaccines per se completely. In fact, among twenty vaccines which need cold chain storage and transport and to be monitored during the whole process, each vaccine has different stability. An ideal time-temperature indicator should be an individualized time-temperature indicator adequately reflecting the thermal stability of the product indicated, i.e. the rate of colour change and the temperature effect thereof keep as consistent as possible with the failure process of the product.
Therefore, in the art there is still a need for a time-temperature indicator and method for monitoring the thermal history of thermally sensitive articles, which are used for monitoring the storage and transport of thermally sensitive articles, and for accurately indicating whether a thermally sensitive article has failed or deteriorated.